The aim of this project is to find new treatments for the most common type of ovarian cancer, high-grade serous ovarian cancer. To achieve this aim, scientists in Italy, USA and the UK will collaborate to exploit and merge their recent discoveries and novel technologies.
The Cavallaro group in Italy has found new ways to identify ovarian cancer stem cells. These elusive cells form the foundation of the cancer, giving rise to the other malignant cells. Since they can be resistant to standard treatments, ovarian cancer stem cells contribute significantly to ovarian cancer spread and relapse. If we are to improve patient outcomes, we must find new treatments that target these stem cells.
Tumors are not just masses of malignant cells. They are complex ‘rogue’ tissues, in which malignant cells recruit and corrupt normal cells to help the cancer grow and spread. We call the normal cells adjacent to cancer cells the tumor microenvironment. It is now clear that to successfully treat cancers we have to understand and prevent the support this microenvironment gives malignant cells. However, we know very little about how ovarian cancer stem cells are supported by the tumor microenvironment. In this context, it is especially important to discover how the stem cells interact with cells of the immune system, which should be capable of recognising and destroying malignant cells. There are many immune cells in close proximity to malignant cells, but, in most cancers, they seem to be ‘disabled’ by the malignant cells.
The Lengyel and Balkwill groups have developed new models and techniques that will allow them to study, for the first time, how ovarian cancer stem cells interact with other cells in their tumor microenvironment. The three collaborating groups will then use high-throughput screening to identify drugs, or combinations of drugs, that will not only eliminate ovarian cancer stem cells, but will neutralize the other cells in the ‘corrupted’ tumor microenvironment, so that they will no longer support stem cell growth, spread, and resistance to chemotherapy.
We believe that this program of research will be a first and fundamental step toward finding a new generation of effective drugs that will improve survival and quality of life for women with ovarian cancer.
Ugo Cavallaro graduated summa cum laude in Biological Sciences from the University of Florence, Italy, and then got his PhD in Experimental Pathology from the University of Milan, Italy. After a few years at the Department of Biological and Technological Research, Scientific Institute H San Raffaele, Milan, under the supervision of Marco Soria, he joined the group of Gerhard Christofori, first as a postdoc at the Research Institute of Molecular Pathology in Vienna, Austria, and then as an Assistant at the Institute of Biochemistry and Genetics, Basel, Switzerland. Dr. Cavallaro went back to Italy in 2003, when he was appointed as a junior group leader at the FIRC Institute of Molecular Oncology (IFOM, Milan). He then joined the European Institute of Oncology, Milan, where is now the Director of the Unit of Gynecological Oncology Research.
Dr. Cavallaro is a cell biologist and biochemist by training, and most of his initial research has been devoted to unravelling novel signaling properties of cell adhesion molecules (CAM). In particular, Dr. Cavallaro uncovered the interplay between immunoglobulin-like cell adhesion molecules and receptor tyrosine kinases (RTK), reporting for the first time the ability of NCAM to act as a noncanonical ligand for FGFR and the implication of such interaction in ovarian cancer progression. Dr. Cavallaro’s group was also the first to describe the aberrant expression of L1CAM, known as a neural CAM, in tumor-associated blood vessels, where L1CAM contributes to neovascularization and endothelial dysfunction. More recently, Dr. Cavallaro’s studies contributed to the discovery of a novel, endothelium-specific isoform of L1CAM which is enriched in ovarian cancer vasculature and contributes to tumor angiogenesis.
In the last few years, Dr. Cavallaro’s Unit of Gynecological Oncology Research became part of the Gynecological Oncology Program of the European Institute of Oncology, which fostered a close collaboration and synergy with the clinical staff of the Program itself. This enabled Dr. Cavallaro’s Unit to establish a biobank of ovarian cancer patient-derived specimens. The latter represented an outstanding resource to address clinically relevant questions in appropriate experimental models. In particular, the Unit is focusing on the role of cancer stem cells in ovarian cancer development, recurrence and chemoresistance. In this context, Dr. Cavallaro’s lab recently described the novel role of CD73 as a driver and a potential therapeutic target in ovarian cancer stem cells. In line with the objective of establishing clinically relevant models, the OCRA-supported project will aim at incorporating primary ovarian cancer stem cells into patient-derived three-dimensional organotypic cultures that recapitulates the tumor microenvironment. These new models will then be harnessed to pursue three main goals: a) define the molecular players of ovarian cancer stemness, tumor initiation and chemoresistance; b) unravel the biological basis of immune escape in ovarian cancer stem cells; c) establish a high-throughput screening platform to identify drugs that specifically target ovarian cancer stem cells and their interaction with the tumor microenvironment. Thus, the project is well positioned not only to shed light on the pathophysiological role of cancer stem cells in ovarian cancer but also to provide insights for innovative therapeutic strategies for the eradication of such a devastating disease.